Allelic deletions in the long arm of chromosome 12 identify sites of candidate tumor suppressor genes in male germ cell tumors.
Allelic deletions in the long arm of chromosome 12 identify sites of candidate tumor suppressor genes in male germ cell tumors.
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DOI：
10.1073/pnas.89.22.11006
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发表时间：
1992-11
影响因子：
11.1
通讯作者：
V. Murty;J. Houldsworth;S. Baldwin;V. Reuter;W. Hunziker;P. Besmer;G. Bosl;R. Chaganti
中科院分区：
文献类型：
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作者：
V. Murty;J. Houldsworth;S. Baldwin;V. Reuter;W. Hunziker;P. Besmer;G. Bosl;R. Chaganti
人类男性生殖细胞肿瘤（gct）是由减数分裂前或减数分裂早期生殖细胞的恶性转化引起的，并表现出三个生发层的胚胎样分化。gct分化表型的起源和表达的遗传基础尚不清楚。我们最近对大量gct的细胞遗传学分析表明，两条12号染色体异常，一条短臂同工染色体[i(12p)]和一条长臂缺失[del(12q)]是这些肿瘤的特征，这使我们认为缺失代表了一个或多个候选肿瘤抑制基因的缺失，这些基因的产物调节着精原干细胞的正常增殖。我们通过比较45例GCT患者配对的正常/肿瘤DNA样本中的8个多态性位点的种系和肿瘤基因型，对缺失进行了分子定位。对这些位点的结构杂合性缺失的分析显示，12q13和12q22是两个频繁缺失的区域（bbb40 %），确定了假定的肿瘤抑制基因的位置。1个肿瘤（没有）。143A)显示了12q22区域的纯合缺失，其中包括MGF基因。KIT和MGF基因已被证明在生殖细胞的胚胎和出生后发育中起关键作用；因此，我们在3个GCT细胞系和24个新鲜GCT活检中通过Northern blot分析评估了它们的表达。观察到半细胞瘤和非半细胞瘤病变中MGF和KIT的表达不一致。
Human male germ cell tumors (GCTs) result from malignant transformation of premeiotic or early meiotic germ cells and exhibit embryonal-like differentiation of the three germinal layers. The genetic basis of origin and expression of differentiated phenotypes by GCTs are poorly understood. Our recent cytogenetic analysis of a large series of GCTs has shown that two chromosome 12 abnormalities, an isochromosome for the short arm [i(12p)] and deletions in the long arm [del(12q)], characterize these tumors, which led us to suggest that the deletions represent loss of one or more candidate tumor suppressor genes whose products regulate the normal proliferation of the spermatogonial stem cells. We undertook a molecular mapping of the deletions by comparing germ-line and tumor genotypes of eight polymorphic loci in paired normal/tumor DNA samples from 45 GCT patients. Analysis of loss of constitutional heterozygosity at these loci revealed two regions of frequent loss (> 40%), one at 12q13 and the other at 12q22, identifying the sites of the postulated tumor suppressor genes. One tumor (no. 143A) exhibited a homozygous deletion of a region of 12q22, which included the MGF gene. The KIT and MGF genes have been shown to play key roles in embryonal and postnatal development of germ cells; therefore, we evaluated their expression by Northern blot analysis in a panel of three GCT cell lines and 24 fresh GCT biopsies. Deregulated expression of MGF and KIT, which was discordant between seminomatous and nonseminomatous lesions, was observed.